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Method for the synthesis of peptides without solvent

a peptide and solvent technology, applied in the field of synthesis of peptides without solvent, can solve the problems of increasing the amount of solvent required, many development problems, and the field of “green chemistry” is becoming more extensive, so as to facilitate the application of reaction reaction, suppress the use of solvent, and treat

Inactive Publication Date: 2011-06-14
CENT NAT DE LA RECHERCHE SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach significantly reduces solvent usage, facilitates reaction application, and enables the production of very pure peptides, aligning with green chemistry principles by eliminating solvent-based waste and improving bioavailability of therapeutic peptides.

Problems solved by technology

In spite of well-established production procedures (in solution, in a solid phase, by recombination), there still subsists many development problems associated with the enormous amount of solvent required for the synthesis, notably on solid supports (2,000-5,000 kg for a large peptide).
The field of “green chemistry” is becoming more extensive because of the seriousness of present environmental problems.
Nevertheless, no application of these techniques to fields such as peptide or amino acid synthesis has been undertaken, in spite of the importance of these biomolecules.

Method used

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  • Method for the synthesis of peptides without solvent
  • Method for the synthesis of peptides without solvent
  • Method for the synthesis of peptides without solvent

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Dipeptides

[0060]The inventors have conducted the reaction without any solvent between a UNCA and an amino acid derivative in order to form a dipeptide according to the equation below:

[0061]

[0062]This reaction was tested in the Boc-Val-NCA, Fmoc-Val-NCA and Boc-Phe-NCA (1 eq.) coupling with various amino acids (1 eq.) in the presence of NaHCO3 (1.5 eq.) in a quenched steel tank containing steel balls. The tank was stirred for 1 hour at a frequency of 30 Hz. The analysis of the reaction medium detected the exclusive existence of the dipeptide. The results are reported in Table 1 with various UNCAs and amino acid derivatives.

[0063]

TABLE 1Conver-YieldUNCAAmino acidsDipeptidession (%)(%)Boc-Val-HCl•H-Leu-OMeBoc-Val-Leu-OMe10087NCAHCl•H-Leu-OButBoc-Val-Leu-OBut9785HCl•H-Ala-OMeBoc-Val-Ala-OMe100100HCl•H-Ala-OButBoc-Val-Ala-OBut100100HCl•H-Phe-OMeBoc-Val-Phe-OMe10088Fmoc-Val-HCl•H-Leu-OMeFmoc-Val-Leu-OMe90—NCAHCl•H-Leu-OButFmoc-Val-Leu-OBut92—HCl•H-Ala-OMeFmoc-Val-Ala-OMe10076...

example 2

Synthesis of Aspartame

[0066]Aspartame, or α-L-aspartyl-L-phenylalanine-methyl ester, is a nutritive sweetener approximately 150 times more intense than saccharose. This is a commercially attractive dipeptide which however has not yet been prepared via UNCAs, neither in the presence nor in the absence of solvent.

[0067]The inventors obtained the protected aspartame in a step from H-Phe-OMe.HCl (III-e) and from Boc-Asp(O-t-Bu)—NCA (II-a) by ball-milling without any solvent.

[0068]The protective groups Boc and t-Bu were selected since they may be cleaved at the same time under acid conditions. In order to further avoid the use of any solvent, HCl gas was used for removing the protective groups.

[0069]2.1. Preparation of Boc-Asp(O-tBu)—NCA (II-a)

[0070]This method consisted in the cyclization of the free carboxylic acid with a main chain with one of the Bocs protecting the amine function, therefore first of all requiring the preparation of (Boc)2-Asp(O-t-Bu)—OH (VII-a). This was achieved by...

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Abstract

The disclosure relates to a method for the synthesis of a compound of the formula (I) in which: n is an integer higher than or equal to 1; Rb and each Rn are independently a hydrogen atom, a C1-C6 arylalkyl group or a C1-C6 alkyl group substituted or not by an aryl group, —COOH, C1-C6, —COO-(alkyl), —CONH2, —SH, heteroaryl, —NH2, —NHC(NH)(NH2), C1-C6-s-(alkyl), —OH or phenol; Ra is a N-protective group; Rc is a ORd group in which Rd is a C1-C6 alkyl group or a NReRf group in which Re and Rf Re independently an N-protective group.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a National Phase Entry of International Application No. PCT / EP2008 / 053444, filed on Mar. 21, 2008, which claims priority to French Application No. 0753970, filed on Mar. 21, 2007, both of which are incorporated by reference herein.BACKGROUND AND SUMMARY[0002]The present invention relates to a method for the synthesis of peptides without any solvent.[0003]Peptides are presently considered as pharmaceutical active ingredients because of their high therapeutic index and their low toxicity. Because of the development of novel administration systems which increase their bioavailability, it is expected that the market of therapeutic peptides will rapidly develop during future years. But there always exists a need for effective methods for synthesizing these compounds. In spite of well-established production procedures (in solution, in a solid phase, by recombination), there still subsists many development problems associated...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07C229/00
CPCC07K1/06C07K1/061C07K5/06078C07K5/0613C07K5/06052Y02P20/55
Inventor MARTINEZ, JEANLAMATY, FREDERICDECLERCK, VALERIE
Owner CENT NAT DE LA RECHERCHE SCI